An important mechanism underlying neuropathic pain is plastic changes in spinal cord dorsal horn neurons, in that they change sensitivity to peripheral inputs. Such changes include increases or decreases in efficacy of afferent synaptic inputs, often called spinal LTP and LTD (sLTP and sLTD) because these physiological phenomena are similar to the long term potentiation (LTP) and long term depression (LTD) extensively studied in the hippocampus. We hypothesize that nociceptive peripheral input induces sLTP in spinothalamic tract neurons (STTn) but sLTD in GABAergic inhibitory interneurons (GABAn). This cell-type specific synaptic plasticity is mediated by cell-type specific intracellular signaling mechanisms caused by two different free radicals that, in turn, are due to differences in iron content of these different cell types. Three specific aims test this hypothesis Specific aim 1 tests the hypothesis that nociceptive input causes NMDA receptor-mediated intracellular calcium influx which leads to sLTP in STTn but sLTD in GABAn in the spinal cord. Single cell patch recordings will be made from identified STTn (labeled with a retrogradely transported dye) and GABAn (using a transgenic mouse whose GABAn are tagged with green fluorescent protein) in spinal cord slices. Specific aim 2 is to test the hypothesis that the same nociceptive input to the spinal cord induces sLTP in STTn but sLTD in GABAn because two different intracellular signaling free radicals are involved, superoxide and hydroxyl radical, respectively. Specific aim 3 is to test the hypothesis that GABAn contain high levels of iron, in turn causing over-production of hydroxyl radicals via superoxide-driven Fenton chemical reactions, and that this over-production then produces sLTD in GABAn. This hypothesis of cell-type and free radical-type specific synaptic plasticity may explain why nerve injuries often lead to chronic neuropathic pain. If proven to be true, this proposal may lead to several avenues for treating chronic neuropathic pain. PUBLIC HEALTH RELEVANCE: This proposal hypothesizes that nociceptive input to the spinal cord induces long term synaptic enhancement in projection neurons but long term synaptic depression in inhibitory interneurons. This dichotomy may explain why nerve injuries often lead to chronic neuropathic pain. If proven to be true, this proposal may lead to several avenues for treating chronic neuropathic pain.